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The hippocampus is particularly vulnerable to metabolic stress, yet the precise molecular mechanisms linking systemic metabolic dysfunction to cognitive decline remain unclear. High-mobility group box 1 (HMGB1), a damage-associated molecule, is elevated in MetS. However, its specific role in simultaneously regulating hippocampal neuronal ferroptosis and microglial activation is poorly defined. Here we show that HMGB1 exacerbates MetS-associated cognitive impairment by promoting both neuronal ferroptosis and microglial inflammation. Using a high-fat high-glucose diet mouse model and primary co-cultures, we found that HMGB1 neutralization alleviated cognitive deficits, reduced neuronal ferroptosis, and suppressed microglial activation. Mechanistically, extracellular HMGB1 acts through neuronal toll-like receptor 4 (TLR4) to trigger the ubiquitination and degradation of nuclear factor erythroid 2-related factor 2 (NRF2). This HMGB1-induced loss of NRF2 impairs autophagic flux, thereby aggravating ferroptosis and neuroinflammation. Furthermore,\u00a0in vitro\u00a0conditioned medium experiments revealed a reciprocal pathological aggravation, where ferroptotic neurons and activated microglia both secrete HMGB1 to exacerbate each other's pathological state. These findings position HMGB1 as a pivotal mediator linking metabolic stress specifically to neuronal ferroptosis and neuroimmune activation. Targeting the HMGB1-NRF2-autophagic flux axis therefore offers a promising therapeutic strategy for mitigating cognitive impairment in patients with MetS.<\/jats:p>","DOI":"10.1186\/s43556-026-00548-8","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:02:47Z","timestamp":1787007767000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HMGB1\u00a0aggravates neuronal ferroptosis and microglial inflammation in metabolic syndrome-associated cognitive impairment via the NRF2-autophagic flux axis"],"prefix":"10.1186","volume":"7","author":[{"given":"Xin","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Meng","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Mei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Qin","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Jun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cun-Ming","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6506-5685","authenticated-orcid":false,"given":"Min","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"issue":"5","key":"548_CR1","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1007\/s00424-024-03051-7","volume":"477","author":"I Pigeot","year":"2025","unstructured":"Pigeot I, Ahrens W. 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